Models have been previously developed by which mice bearing a disseminated leukemia can be cured with a combination of nonlethal, noncurative chemotherapy and adoptively transferred syngeneic immune lymphocytes. The major goal of this project has been to identify the effector mechanisms operative in vivo by which such adoptive chemoimmunotherapy (ACIT) results in tumor destruction. In studies on the potential role of cytotoxic T cells (CTL) in eradicating disseminated tumors, purified subpopulations of immune Lyt 1+2- cytolytic T cells, which had been rendered cytolyt-ically active by secondary in vitro sensitization, were used in ACIT of disseminated FLB-3 leukemia. These CTL, which exhibited a high degree of specific cytotoxicity to FBL-3 in vitro, mediated a potent therapeutic effect in vivo. Moreover, their activity was enhanced by concurrent infusion of amplifier Lyt 1+2- T cells. Thus, CTL have a definite therapeutic potential in adoptive therapy and this potential may be enhanced by administration of amplifier cells. In studies on the potential role of delayed-type hypersensitivity (DTH) in tumor elimination by ACIT T-deficient adult thymectomized mice, infusion of purified immune donor noncytolytic Lyt 1+2- T cells produced a substantial therapeutic effect. DTH is presumably the important immunological effector mechanism since infused antibody has no significant activity in this model and there are no host or donor CTL or CTL precursors present. We are now re-examining the immunological composition of the T-deficient hosts surviving long-term after therapy with Lyt 1+2- T cells. Studies on the analysis of host and donor T cells with congenic mice have thus far revealed that a small population of donor T cells persist for more than 100 days after cell transfer in ACIT, and that this small population of donor cells represents the majority of tumor-reactive T cells present in the host even long after adoptive therapy. Preliminary studies on infusion of IgG monoclonal antibodies which recognize the Thy antigen expressed on either the host or congenic donor T cells, and which have been shown to deplete T cells in vivo, suggest that donor T cells must persist for greater than 1 week after cell transfer to be effective, that host T cells contribute to tumor eradication during the first week after ACIT (possibly due to cyclophosphamide-resistant short-lived CTL and CTL precursors), and that host T cells contribute minimally to tumor eradication after the first week following therapy. The goal for the coming year is to identify the contribution of host and donor T cells in adoptive therapy.